Synthesis of 2-Amino-<i>N</i>′-aroyl(het)arylhydrazides, DNA Photocleavage, Molecular Docking and Cytotoxicity Studies against Melanoma CarB Cell Lines
Achilleas Mitrakas,
Maria-Eleni K. Stathopoulou,
Chrysoula Mikra,
Chrystalla Konstantinou,
Stergios Rizos,
Stella Malichetoudi,
Alexandros E. Koumbis,
Maria Koffa,
Konstantina C. Fylaktakidou
Affiliations
Achilleas Mitrakas
Laboratory of Cellular Biology, Molecular Biology and Genetics Department, Democritus University of Thrace, University Campus, 68100 Alexandroupolis, Greece
Maria-Eleni K. Stathopoulou
Laboratory of Organic, Bioorganic and Natural Product Chemistry, Molecular Biology and Genetics Department, Democritus University of Thrace, 68100 Alexandroupolis, Greece
Chrysoula Mikra
Laboratory of Organic Chemistry, Faculty of Chemistry, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
Chrystalla Konstantinou
Laboratory of Organic, Bioorganic and Natural Product Chemistry, Molecular Biology and Genetics Department, Democritus University of Thrace, 68100 Alexandroupolis, Greece
Stergios Rizos
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford St., Cambridge, MA 02138, USA
Stella Malichetoudi
Laboratory of Cellular Biology, Molecular Biology and Genetics Department, Democritus University of Thrace, University Campus, 68100 Alexandroupolis, Greece
Alexandros E. Koumbis
Laboratory of Organic Chemistry, Faculty of Chemistry, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
Maria Koffa
Laboratory of Cellular Biology, Molecular Biology and Genetics Department, Democritus University of Thrace, University Campus, 68100 Alexandroupolis, Greece
Konstantina C. Fylaktakidou
Laboratory of Organic, Bioorganic and Natural Product Chemistry, Molecular Biology and Genetics Department, Democritus University of Thrace, 68100 Alexandroupolis, Greece
Diacylhydrazine bridged anthranilic acids with aryl and heteroaryl domains have been synthesized as the open flexible scaffold of arylamide quinazolinones in order to investigate flexibility versus rigidity towards DNA photocleavage and sensitivity. Most of the compounds have been synthesized via the in situ formation of their anthraniloyl chloride and subsequent reaction with the desired hydrazide and were obtained as precipitates, in moderate yields. All compounds showed high UV-A light absorption and are eligible for DNA photocleavage studies under this “harmless” irradiation. Despite their reduced UV-B light absorption, a first screening indicated the necessity of a halogen at the p-position in relation to the amine group and the lack of an electron-withdrawing group on the aryl group. These characteristics, in general, remained under UV-A light, rendering these compounds as a novel class of UV-A-triggered DNA photocleavers. The best photocleaver, the compound 9, was active at concentrations as low as 2 μΜ. The 5-Nitro-anthranilic derivatives were inactive, giving the opposite results to their related rigid quinazolinones. Molecular docking studies with DNA showed possible interaction sites, whereas cytotoxicity experiments indicated the iodo derivative 17 as a potent cytotoxic agent and the compound 9 as a slight phototoxic compound.
